There is accumulating evidence that an intimate relationship exists between the lytic cycle and the cell cycle, not only with EBV but also other herpesviruses. Our recent preliminary studies show that not only does EBV regulate the cell cycle during the lytic replication cycle but that reactivation is regulated by cell cycle control pathways. This form of regulation likely evolved as a strategy to ensure that entry into the lytic replication phase ensues only if the virus detects that the cell is in a favored status for optimal viral replication (i.e. growth arrest). The aims outlined in this proposal are directed towards investigating the molecular mechanisms through which cell cycle control proteins govern viral reactivation. Specifically, we will investigate the control of the immediate early promoter, Zp (the BZLF1 promoter), by the cell cycle regulatory protein, c-Myc, which is known to be modulated during viral reactivation. In addition, we will assess the role that c-Myc plays in regulating the transcriptional activation properties of the immediate early transactivator, Zta (the protein product of BZLF1). Together, these studies should further our understanding of the intimate relationship between lytic replication in herpesvirus and the cell cycle. In addition, they will provide insights into the transcriptional control mechanisms involved in regulating the transition from latency to committed engagement of the lytic replicative phase of the viral life cycle.